Block A Flashcards
(63 cards)
1
Q
Gut Signalling
A
Stimuli from lumen detected and signal transmitted via:
- immune
- endocrine hormones: local and circulating
- neural: intrinsic and extrinsic
2
Q
Sensation in the gut
A
- IPANs
- Intestinofugal neuron
- Primary afferent vagal neurons
- Primary afferent spinal neurons
3
Q
IPANS
A
Responds to:
- Luminal chemical stimuli
- Mechanical deformation of mucosa
- Stretch
4
Q
Intestinofugal neurons
A
- Small portion of cholinergic neurons (ACh)
- Project from myenteric ganglia to the sympathetic ganglion
- Short inhibitory reflex pathways
5
Q
Vagal Afferents
A
- 75% of fibres in the vagus are afferent
- Most precent in the proximal gut, with terminals found in all layers
- Cell bodies lie in the nodose ganglia and project to brainstem
- activated by physiological levels of distention and released hormones
6
Q
Spinal afferents
A
- predominate in the distal GIT, with terminal found in the muscle, submucosa and serosa
- have cell bodies in the DRG and synapse in the dorsal horn of the SC
- Encodes physiological AND noxious levels of stimulation
7
Q
Types of Secretory Glands
A
- Exocrine: ducts
- ENdocrine: bloodstream
8
Q
ENteroendocrine cells
A
- Hormone producing cells in the gut
- Located in epithelial glands
- Activated by: neural stim and luminal changes
- Long apical microvilli ‘taste’ luemn
- Granules released from basolateral memb into capillaries or stimulate cells locally
9
Q
Gut hormones
A
- Peptides
- Released from pancreas, stomach, intestines
10
Q
Hormone Signal Transduction
A
- Bind to memb surface receptors (GPCRs)
- activated g protein -> second messenger generation such as cAMP and IP3 -> calcium release (triggers exocytosis)
11
Q
2 major actions of endocrine signalling
A
- stimulate effector cells to secrete contents
2. activate afferent neurons to connect signal with deeper layers of the gut or cns
12
Q
Gastrin
A
- released from g cells in pyloric gland mucosa
- released stimulated by neural, nutrient and ph
- major role in control of gastric acid secretion
- aa’s binding to CaR can stimulate release of gastrin
13
Q
CCK2 Receptor
A
- Main ligand of cck2 in CNS is cck
- Main ligand for cck2 in PNS is gastrin because much higher concentration
14
Q
- Stomach Acid Secretion
A
- cephalic phase (30): stimuli orginates in head
15
Q
- Stomach Acid Secretion
A
- gastric phase (50): stimuli originates in stomach
- luminal ph rises allowing vagally mediated gastrin release
- Luminal peptides stimulate gastrin release
- distension activates mechanoreceptors
- caffeine stimulates acid release directly by acting on parietal cells
16
Q
- Stomach Acid Secretion
A
- intestinal phase (10): stimuli originates in duodenum
- protein digestion stimulates acid secretion via intestinal gastrin
Inhibition of acid release:
- enterogastric reflex: sympathetic activity opposes vagal stim -> intrinsic nerves inhibited
- enterogastrone reflex: hormones inhibit gastric secretion and motility
- low pH triggers release of somatostatin
17
Q
H. Pylori Infection
A
- Infection impairs notmal acid-mediated inhib control of gastrin release
- Healthy un-inflamed mucosa secretes excess acid
- gastrin exerts trophic levels on mucosa (increasing ECL and parietal cells)
- Increased acid load in duodenum
- Increased gastric acid -> ulceration
- Decreased gastric acid -> atrophic gastrisits and gastric cancer
18
Q
Neurocrines
A
- peptides released by nerves causing a physiological response in the gut
19
Q
VIP
A
- neurocrine
- acts on enterocytes, SM cells and blood vessels
- relax GI SM
- Vasodilation
- Stimulates electrolyte secretion in the gut
20
Q
Water movement
A
- in repsonse to osmotic forces
- main driving force in the intestine is transcellular chloride secretion via CFTR
- mainly from crypt cells
- Na follows paracellularly, resultant NaCl in lumen = osmotic drive for water
21
Q
Secretomotor neurons
A
- Excitatory neurons of ENS
- cell bodies in the submucosal plexus
- Cholinergic ( release ACh) and non-cholinergic (release VIP) -> triggers chloride secretion
- Collateral projections from the axons innervate submucosal arterioles (ACh acts on BV to release NO -> dilation) to link activity in the glands with submucosal blood flow
22
Q
SMN Reflex - noxious stimuli
A
- (5-HT and PG) IPANS -> (ACh) interneuron -> (ACh) BV SM (vasodilation) AND SMN -> VIP and ACh -> increase chloride secretion
23
Q
Summary of SMN regulation
A
- Large volumes of water are absorbed into lamina propria with nutrients - secretomotor reflexes return water to lumen
- Gut hormones released in reponse to glucose (L+GLP-2) activate secretomotor neurons
- SM reflex moves water from interstitium and circulation
- balance of fluid exchange is modulated by:
- sympathetic vasoconstrictor and SM inhib pathways determined by whole body fluid status
- intrinsic neural restraint
- endocrine inhibitors (PP family)
24
Q
Cholera toxin
A
- Epithelial: uncontrolled levels of cAMP and PKA -> constant opening of CFTR channels -> uncontrolled secretion of chloride -> water follows chloride -> secretory diarrhoea and dehydration
- Neurogenic: toxin activated enteroendocrine cells to release 5-HT -> activates intrinsic sensory neurons -> interneurons -> SMN -> VIP and ACh -> increased chloride secretion
25
Diarrhoea management
- target neuroendocrine pathways
| - drugs: synthetic opiates (loperamide), somatostatin analogues (octreotide)
26
Glucose transporters
- SGLT1 is a symport carrier (secondary active transport) that uses the sodium concentration gradient established by Na/K ATPase to move sodium inwards (from lumen to cell)
- Monosaccharides leave cell down a concentration gradient via facilitated diffusion through GLUT2 (from cell to blood)
- SGLT1 is a six state carrier
- Inhibition of SGLT1 with phlorizin prevents glucose uptake to blood
- SGLT1 is also expressed by enteroendocrine cells and is required for release of insulinotropic hormones
27
SGLT1 Deficiency
- a rare autosomal recessive genetic disorder
- mutations result in either truncated SGLT1 protein or mistrafficking of transporter in cell
- GGM is characterised by neonatal onset of watery and acidic severe diarrhoea, which is fatal within a few weeks unless lactose (glucose and galactose) is removed from the diet
28
GLUT2
- can also absorb glucose from the lumen
| - inserted into the apical membrane in response to high glucose concentrations
29
Intestinal defence mechanisms
1. epithelium: selective barrier
2. secretions: mucus, anti-microbial peptides
3. GALT
4. Microbiota
30
Secretions
Epithelial origin:
- mucous (protection)
- anti-microbial factors from Paneth cells: innate immunity, granules are released in response to cholinergic and bacterial signals
Immune Origin:
- Immuniglobulin (mainly IgA)
- Derived from serum (enter interstitium via fenestrated capillaries)
- Main role is to defend mucosal surface form environmental microbes:
- Steric hinderance: prevents adhesion of bacteria to epithelium by creating competitive binding sites
- immune exclusion: series of events including agglutination, entrapment and clearance
31
Secretory IgA
Defends mucosa in 4 ways:
1. function as blocking antibodies at mucosal surface
2. Intracellular neutralisation of infecting viruses
3. Intracellular neutralisation of endotoxin j- prevents pro-inflam cascade
4. Stromal clearance of antigens that have breached mucosa
32
GALT
- Mesenteric lymph nodes
- Peyer's patch and isolated lymphoid follicles
- Function to distinguish between innocuous and pathogenic micro-organisms and elicit appropriate response
33
Microbiome
- combined ecological community of commensal, symbiotic and pathogenic micro-organisms that share our body space
34
Benefits of microbiome
- Nutrition: ferment non-digestable fibre and synthesiser vitamins
- Defence and immune development:
- Inhibits new colonisers through competition for nutrients and receptors
- Producing bacteriocins and pH modification of luminal environment ( sot hat the ph is more suited to commensals than the pathogenic species)
35
PRRs
- Epithelial cells, enteroendocrine and antigen-presenting cells all express pattern recognition receptors (recognise pattern associated molecular patterns)
- role is to discriminate between pathogens and commensal and elicit appropriate responses
- PRRs may be on surface or intracellular
Binding of PAMPs to:
- macrophage PRR -> secretion of cytokines or pahgocytosis
- dendritic cell PRR -> maturation, migration to MLN to present to B and T cells
36
TLR/PRRs structure
- Ligand binding domain: highly specific for the ligand
- Intracellular domain is highly conserved between all different types of TLRs, therefore all have similar intracellular signalling cascades
37
TLR Signalling
- Signal initiated by ligand binding -> receptor dimerisation
- Predominant signalling cascade via MyD88
- Activates NFKB and MAPK transcription factors
- Increased expression of genes that regulate inflammation (innate immunity), immune cell recruitment, adhesion molecules and other mediators -> pathogen clearance
- Triggers adaptive immunity
38
TLRs: Physiological Roles
TLR signalling in health contributes to immune homeostasis in 4 ways
1. regulation of immune tolerance to commensals ('immunosuppressive tone)
2. regulation of SIgA and antimicrobial peptides (TLR/commensal interaction increase Paneth cell secretion and cytokines -> B cell secrete non-specific IgA)
3. Cytoprotection (increase barrier function by sealing tight junctions)
4. Epithelial proliferation (TLRs activate growth signalling to initiate healing)
39
Mast cells
- part of innate immune system
- found throughout gut mucosa
- tightly associated with intrinsic and extrinsic endings
- release an array of cytokines, GFs and other mediators: act on ep cells to alter secretion and perm, and stim enteric neurons
- bi-directional relationship
- effector cells of the brain-gut axis (implicated in IBS/stress)
40
Stress and the intestine
- Functional effects: increased ion and water secretion, mucin release and perm
- Mechanisms:
- neural: CRH and ACh
- immune: mast cells
41
Parasites and inflammation
- data supports hypothesis that a reduction in helminth infection during childhood is linked to a rise in the incidence of autoimmune diseases
- Helminths are immunoregulatory to avoid immune overreaction during infection
42
Luminal glucose sensing: link to neurons
1. sweet taste cell are activated by microvilli receptors 'tasting' bd products of carbohydrates
2. release of cell products activates local vagal afferents in a paracrine manner
3. reflexes are triggered that alter behaviour (feeding) and slow gastric emptying
43
Tasting glucose in the gut lumen
| GPCRs
Sweet taste cells posses signal transduction machinery
1. sweet taste receptors comprising the GPCR T1R3 detect a wide range of sweet tastants in the lumen
2. Upon GPCR binding, the taste-specific G-protein Gusducin is activated, leading to activation of PLCbeta2
3. This leads to the release of intracellular calcium from IP3-sensitive stores
4. rising intracellular calcium can then gate the taste specific cation channel TRPM5, leading to Na influx, membrane depolarisation, and neuromediator release
5. Nerve terminal activation
44
Tasting glucose in the gut lumen
| L cells
- L cells detect glucose levels -> secrete GLPs
- At low glucose levels , cell membrane is hyperpolarised (ATP-gated potassium channels are open, allowing efflux of ions)
- At high glucose levels, cell membrane depolarises (increased intracellular glucose -> ATP production -> increased ATP/ADP ratio -> closing of ATP-sensitive K channels in cell memb -> membrane depol -> opening of voltage-gated calcium channels, calcium carrying memb potentials and stimulation of exocytosis)
45
Tasting glucose in the gut lumen
| SGLT1
- SGT1 transport of glucoses with Na current
- Net influx of Na current causes depolarisation -> GLP-1 secretion
- Inhibition of SGLT1 prevents GLP-1 release in response to glucose meal
- Expression of SGLT1 and GLUT2 is increased in response to sweet ligands via sweet taste receptor mechanism
46
Nutrient sensing in SI and appetite regulation
- Mechanoreceptors, changes in circulating nutrient concentration, release of anorectic gut hormones (e.g. GLP-1) decrease feeding
- SI sends endocrine satiety signals centrally to the hypothalamus, either directly via the bloodstream or indirectly, through the activation of the vagus nerve
47
Hypothalamus: structure
- ARC is adjacent to the median eminence (MA), which has a leaky BBB -> circulating hormones and nutrients can access directly
48
Arcuate Nucleus (ARC)
- 1st order appetite neurons
- Two distinct population of neurons
1. Express orexigenic (stimulate appetite) neuropeptides: NPY and AgRP
2. Express anorexigenic (decrease appetite) neuropeptides: POMC and CART
- Both of these types of neuropeptides project from the ARC to other hypothalamic nuclei such as PVN and LHA
49
Hypothalamic Nuclei
- second order neurons
- activation of receptors on second order neurons leads to secretion of neuropeptides that modify appetie
1. PVC: inhibits food intake
2. LHA: 'feeding centre' -> increase intake
50
Brainstem involvement in appetite
- the brainstem DVC comprises the nucleus of the NTS, the AP (absence of complete BBB here) and the dorsal motor nucleus of the vagus
- DVC is a communication link between peripheral singals of food intake and hypothalamic nuclei: neural projections from the brainstem to the hypothalamus and vice-versa (bi-directional communication)
- Vagal afferents carry sensory info from the gut directly to the NTS: NTS neurons produce GLP-1, NOY and POMC
51
CCK
- Secreted from I-type enteroendocrine cells in the duodenum
| - Binds to CCK1 receptors on vagus nerve terminal, transferring satiety signals to the hypothalamus via brainstem
52
L cells
- secrete anorectic gut hormones: PYY and GLP-1
- found in SI and colon
- Initial release of hormones is within 15 mins of food intake (ie before ingested nutrients reach the distal SI) .: is likely to be under neural control
- > nutrients in stomach or duodenum stim the release of hormones that act through vagal and ENS pathways to stim L cells
53
PYY
- secreted by L cells
- Stimulated by high fat meal
- inhibits appetite by acting directly on ARC via the Y2 receptor -> increases activity of anorexigenic POMC/alpha-MSH neurons, whilst suppressing orexigenic NPY neurons
54
GLP-1
- secreted by L cells
- released in proportion to the calories ingested, especially carbohydrates and stimulates insulin release
- GLP-1 may produce signals via vagal activation or directly act on central receptors - GLP1 is present in the ARC and PVN in the hypothalamus, and the AP in the brainstem
55
GLP-1 Drugs
- Liraglutide is a GLP1 receptor agonist
| - FDA approved chronic weight management in obesity
56
Apoptosis steps
1. Loss of mitochondiral membrane integrity: releases proteins that initiate apoptosis signalling cascade
2. chromatin condensation and nuclear shrinkage
3. cell shrinkage, loss of cytoskeleton structure
4. formation of apoptotic bodies containing intact organelle
5. phagoctyosis of apoptotic cells and fragments by phagocytes
57
Apoptosis in embyogenesis
Morphogenesis: eliminates excess cells in webbing
58
Apoptosis in adults
- increase in mammary gland cells during pregnancy and lactation
- once no longer needed -> involution (apoptosis of extra cells)
59
Extrinsic apoptotic signalling pathways
Death receptor
- cell membrane receptors (ligand binds)
- death adaptor proteins
- caspases
- inhibitor of apoptosis proteins
60
intrinsic apoptotic signalling pathways
Mitochondrial
- Bcl-2 family
- mitochondrial proteins
- caspases or apoptosis initiating factor
- inhibitor of apoptosis proteins
61
Bcl-2 Famliy
Anti-apoptotic or pro-apoptotic, depended on how many BH domains
- 4 domains = anti-apop
- 1 or 3 = pro-apoptotic
- Move from cytoplasm to mitochondrial membrane on stimulus
- Forms pores in outer mitochondrial membrane, alters permeability (allows entry of molecules)
62
Death receptors
- members of TNF receptor super family
- recruit death adaptor molecules upon ligand binding
Link directly to caspases
63
Caspases
- Proteases found as zymogens (inactive pro enzyme), activated by cleavage at aspartic residues, producing a large and a small subunit
1. Initiator caspases (first step)
- main role: activate more caspases
2. executioner caspases
- cleave substrates in cytoplasm
- activate endonucleases -> DNA fragmentation
